Subunit vaccines present an antigen to the immune system without introducing viral particles in an effort to generate an immune response that is effective against that antigen. Such subunit vaccines are often poorly immunogenic and require co-administration of one or more adjuvants to generate an effective immune response (Perrie, Y., et al., Int. J. Pharm. 364, 272-280 (2008); Zepp, F. Vaccine 28S C14-C24 (2010)). Immunostimulatory oligonucleotides, such as those containing unmethylated cytosine-phosphate-guanine (“CG” or “CpG”) motifs, can be used as an adjuvant to stimulate both cellular and humoral immune responses (Vollmer, J. & Krieg, A. M. Adv. Drug Delivery Rev. 61, 195-204 (2009); Klinman, D. M. Nat. Rev. Immunol. 4, 249-259 (2004)). A challenge to the clinical application of oligonucleotides as a vaccine adjuvant is the lack of an efficient system with which to target the oligonucleotides in vivo to the immune cells of the lymphatic system (Von Beust, B. R., et al. Eur. J. Immunol. 35, 1869-1876 (2005); Bourquin, C., et al., J. Immunol. 181, 2990-2998 (2008)).
Transporting antigens/adjuvants from the location of injection to secondary lymph nodes is challenging and depends upon the complex physiology of the lymphatic system (Pal, I. & Ramsey, J. D. Adv. Drug Delivery Rev. 63, 909-922 (2011); Reddy, S. T., et al., Nat. Biotechnol. 25, 1159-1164 (2007)). Antigens/adjuvants introduced into the body may be taken up by immune dendritic cells (DCs) at the injection site and then carried to lymph node through DC trafficking (e.g., cell associated antigen or larger particles, >200 nm). Alternatively, they could directly enter the lymphatic vessels and drain into the secondary lymphoid organs (e.g., small particles, <200 nm) where a significant portion of the immune cells reside (Bachmann, M. F. & Jennings, G. T. Nat. Rev. Immunol. 10, 787-796 (2010); Reddy, S. T., et al., Nat. Biotechnol. 25, 1159-1164 (2007); Singh, M. Vaccine adjuvant and delivery system. Wiley. (2007); Oyewumi, M. O., et al., Expert Rev. Vaccines 9, 1095-1107 (2010); Cai, S., et al., Adv. Drug Delivery Rev. 63, 901-908 (2011); Manolova, V., et al. Eru. J. Immunol. 38, 1404-1413 (2008)).
Soluble antigen/adjuvant compounds flush through lymph nodes within hours (Pape, et al., Immunity 26, 491-502 (2007)), providing only a brief exposure to the vaccine. Attempts to enhance the delivery of antigens/adjuvants to lymph nodes following parenteral injection have included the use of depot-forming adjuvants or particulate carriers that are preferentially internalized by antigen presenting cells (Johansena, et al., Journal of Controlled Release, 148, 56-62 (2010), Moon, et al., Adv. Mater., 24, 3724-3746 (2012), Bachmann and Jennings, Nat. Rev. Immunol. 10, 787-796 (2010), Hubbel, et al., Nature, 462, 449-460 (2009), Pal, & Ramsey, J. D. Adv. Drug Delivery Rev., 63, 909-922 (2011), Reddy, et al., J. A. Nat. Biotechnol., 25, 1159-1164 (2007), John, et al., Nature Materials, 11, 250-257 (2012)) but these approaches do not achieve the potency of direct injection of vaccines into lymphoid tissues (Senti, et al., Curr. Opin. Allergy Clin. Immunol., 9:537-543 (2009)). Molecularly-targeted vaccines based on the conjugation of antigen to antibodies or other ligands targeting dendritic cells not only reach DCs in the draining lymph nodes, but also drain into the systemic circulation and access DCs in distal tissues (Keler, et al., Oncogene, 26, 3758-67 (2007), Tacken, et al., Nat. Rev. Immunol., 10, 790-802 (2007), Tenbusch, et al., PLoS ONE, 7, e39038 (2012)). Such systemic delivery may promote tolerance unless inflammatory adjuvants are also systemically co-administered, an approach likely to give rise to unacceptable toxicity in prophylactic vaccines.
However, there remains a need for efficient delivery systems to target antigens/adjuvants to lymphoid-residing antigen presenting cells, especially CD8+ DCs, a step that is important for inducing a cytotoxic T lymphocyte (CTL) response as CD8+ DCs are the major DCs capable of cross-presentation (Smith, C. M., et al., J. Immunol. 170, 4437-4440 (2003); Schnorrer, P., et al., Proc. Natl. Acad. Sci. USA 103, 10729-10734 (2006); Bedoui, S., et al., Nat. Immunol. 10, 488-495 (2009)), a process required for presenting extracellular antigens within MHC class I molecules to CD8+ T cells.
Therefore, it is an object of the invention to provide compositions and methods of increasing delivery of vaccine adjuvants to the lymph nodes.
It is also an object to the invention to provide compositions and method for increasing delivery of vaccine antigens to the lymph nodes.
It is another object of the invention to provide immunogenic compositions and methods of use thereof for increasing delivery a combination of vaccine adjuvants and antigens to the lymph nodes.
It is a further object of the invention to provide immunogenic compositions and methods of use thereof for inducing an immune response.
It is another object of the invention to provide compositions and methods for increasing retention of vaccine adjuvants and antigens locally, at the site of administration and ipsilateral draining lymph nodes.
It is a further object of the invention to provide methods for increasing local immune responses.